Evidence of Reoxygenation Injury in CO Poisoning

The fact that cytochrome a-a3 may remain inhibited when a patient is reoxygenated prompts consideration of the formation of free oxygen radicals and the occurrence of reoxygenation injury.

It has long been recognized that there are many similarities between the pathology of brain lesions from CO poisoning and ischemia reperfusion injuries. This has led to a hypothesis that the injuries share a similar pathophysiology as well28-30.

Thom31 showed evidence of the occurrence of lipid peroxidation in brain of CO poisoned rats during reoxygenation. Increase in conjugated dienes and malonyldialdehyde concentrations only appears 90-mins after CO exposure while breathing normal air.

He was further able to demonstrate that blocking xanthine oxidase by allopurinol or depleting animals of this enzyme by feeding them with a tungsten-supplemented diet decreased the magnitude of brain lipid peroxidation32. This offers further evidence that at least in part a common mechanism exists between CO poisoning and reperfusion injury.

Brown and Piantadosi33 reported further evidence for oxygen free radical generation during the reoxygenation phase after CO exposure; They discovered a decrease in brain catalase activity that suggested hydrogen peroxide production with a decrease in the ratio of reduced glutathione and an increase in salicylate hydroxylation products - indicating hydroxyl radical production. Moreover, they were able to demonstrate that this overproduction of oxygen free radical was related to a decrease in intracellular pH and ATP levels.

Apart from these neuronal changes occurring during the reoxygenation phase, Thom showed CO poisoning also caused endothelial - suggesting increased oxidative stress34. These injuries were due to an increase in nitric oxide (NO) generating increased quantities of peroxynitrite with protein nitrotyrosyl formation35 and activation of the caspase pathway leading to increased apoptosis36.

To summarize, CO poisoning harms tissues due to:

- hypoxic hypoxia: a decreased oxygen delivery to tissues as blood oxygen content falls due to COHb formation. Also cardiac output drops due to COMb formation, and there is a leftward shift of the dissociation curve of oxyhemoglobin (HbO2);

- histotoxic hypoxia: a direct toxic effect on the cells from binding to cytochrome a-a3 resulting in a disruption in oxidative phosphorylation and a reduction in ATP production;

- reoxygenation injury similar to ischemia-reperfusion syndrome with the onset of cerebral lipid peroxidation due to the activation of the polymorphonuclear leukocytes; endothelial injury related to the production of peroxynitrites; and the production of other potentially harmful cellular compounds including an increase in the output and reduced uptake of neurotransmitters and excitatory amino-acids. Both these mechanisms can trigger apoptosis in vulnerable cells.

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